The present invention relates to the basic problem that many of the biomedical devices used in contact with live tissue or body fluids are made of materials of synthetic or natural origin which are not biocompatible. Lack of biocompatibility can lead to blood clotting as well as various other manifestations of inflammation and tissue activation.
In addition, microbial infection can establish themselves on device surfaces. Infectious agents such as bacteria that colonize and form biofilms on surfaces can prove exceedingly difficult to eradicate, [Costerton, J. W. et al. (1999) Science 284:1318-1322]. Devices intended for long-term contact such as implanted stents or indwelling catheters can also serve as a surface for host cell adhesion, permitting host cells to become activated, proliferate or to alter normal physiological function and to restrict function or intended use of a device, for example by restricting fluid flow through the device.
An approach used in the prior art to improve biocompatibility has been based on modifying the surface of a device to make it more hydrophobic. On the other hand increased biocompatibility at least in part can be achieved by making a surface more hydrophilic. Although certain types of polymers, such as silicones and siloxanes, are known to possess many attributes of biocompatibility, there are no reliable physical correlates which enable one to predict biocompatibility with any degree of certainty. Generally, hydrophobic surfaces are more biocompatible than hydrophilic surfaces. Zisman""s critical surface tension [Zisman, W. A., (1964) Adv. Chem. Ser. 43] has been used as a parameter to help assess potential biocompatibility. Materials with an optimum critical surface tension are frequently biocompatible, yet there are notable exceptions. For example, polyethylene and polypropylene have critical surface tensions well within the optimum range, but they are not predictably biocompatible. Other factors are also important. Without a clear understanding of the nature of these factors, biocompatibility remains unpredictable.
Because of the attractive structural properties of polyolefins and polyurethanes, various blending and copolymerization techniques have been developed to impart greater biocompatibility. U.S. Pat. No. 4,872,867 discloses modifying a polyurethane with a water soluble polymer and crossing them in situ with a silane-type coupling agent to form a cross-linked and intertwined polysiloxane network. U.S. Pat. No. 4,636,552 discloses a polydimethyl siloxane with polylactone side chains which are said to be useful for imparting biocompatibility when combined with a base polymer, or used to replace plasticizer. U.S. Pat. No. 4,929,510 discloses a diblock copolymer having a more hydrophobic block and a less hydrophobic block. A solution of the diblock copolymer in a solvent which swells the matrix polymer is used to introduce the diblock into an article of matrix polymer. Thereafter, the article is transferred to water, to force orientation of the incorporated diblock copolymer such that the more hydrophobic block is embedded in the matrix and the less hydrophobic block is exposed on the surface of the article. Examples of diblock copolymers included poly (ethyleneoxide-propylene oxide), N-vinyl-pyrrolidone-vinyl acetate and N-vinyl-pyrrolidone-styrene. U.S. Pat. Nos. 4,663,413 and 4,675,361 disclose segmented block copolymers, in particular polysiloxane-polycaprolactone linear block copolymers. The latter were incorporated into base polymer material to modify the surface properties thereof. Although initially blended in bulk into the base polymer, the copolymer migrates to the surface to form an exceptionally thin, possibly a monolayer film which imparts the desired surface characteristic, specifically, biocompatibility.
Triblock copolymers having a polydimethyl siloxane (PDMS) block flanked by polylactone (PL) blocks have been described, Lovinger, A. J. et al. (1993) J. Polymer Sci. Part B. (Polymer Physics) 31:115-123. Such triblock copolymers have been incorporated into bulk formulations, and also applied as surface coatings, to reduce thrombogenicity, as described in U.S. Pat. No. 5,702,823, incorporated herein by reference. PL-PDMS-PL triblock copolymers are commercially available, for example from Thoratec Laboratories, Berkeley, Calif., which provides a series of such polymers designated xe2x80x9cSMAxe2x80x9d in which the siloxane is dimethyl siloxane and the lactone is caprolactone, and also from Th. Goldschmidt AG, Essen Germany, under the name xe2x80x9cTegomerxe2x80x9d (Trademark, Goldschmidt AG). The nominal molecular weights (number average) of the polysiloxane blocks suitable for use herein range from about 1000 to about 5000, while the nominal molecular weights of the caprolactone blocks range from about 1000 to about 10,000. Tsai, C-C. et al (1994) ASAIO Journal 40:M619-M824, reported comparative studies with PL-PDMS-PL blended into polyvinyl chloride and other base polymers or applied as a coating thereon.
Deppisch, R. et al (1998) Nephrol. Dial. Transplant. 13:1354-1359 reported improved thrombogenic properties for films or membrane structures of polyamide-polyvinyl-pyrrolidone, polyamide-polyarylethersulfone-polyvinylpyrrolidone or polyarylether-polyvinylpyrrolidone. Improved thrombogenic properties were attributed to a microdomain surface structure of hydropholic and hydrophilic surface patches.
U.S. Pat. No. 5,589,563 discloses polymers having surface-modifying end groups, for example, polyurethanes having hard segments and soft segments covalently bonded to end groups such as PDMS or aromatic polycarbonates. The surface-modifying end groups tend to concentrate on the polymer surface to increase the surface hydrophobicity.
More recently, it has been recognized that the interactions between biological substances and man-made materials leading to clotting, inflammatory responses and microbial and host cell reactions are more complex processes in which the surface hydrophobicity of the man-made material is but one factor. Interactions between biological materials and foreign substances have been shown to include, at a minimum, molecular interactions with components of the complement system, with the kallikrein-kinin system, with the intrinsic pathway of coagulation initiation, with platelet and with other cellular components of blood including peripheral blood cells, e.g. monocytes and granulocytes.
In addition, microbial growth and host cell activation and/or proliferation on the polymer surface are problems with potentially serious consequences, especially for implanted or indwelling articles such as catheters and stents. The design of materials having improved biocompatibility must take such factors into account.
The invention includes a co-polymer film and method for improving the biocompatibility of any article of synthetic/polymeric, organic or metallic origin intended to contact blood, tissue or body fluids in the course of a medical treatment or procedure. Such articles include, without limitation, tubing, bags, catheters, stents, probes, feeding tubes, drainage lines, vascular grafts, artificial shunts and the like whether intended for long-term or short-term contact with blood, tissue or other body fluid or their plasma or corpuscular and cellular constituents. The co-polymer film of the invention provides reduced thrombogenicity, reduced bacterial growth and adhesion, reduced toxicity to host cells, and infiltration and seeding with inflammatory cells or host cells, when compared to articles or materials in conventional use or without the polymer film described.